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PLoS Neglected Tropical Diseases May 2021Anthelminthic treatment options against schistosomiasis are limited. The current treatment relies almost exclusively on a single drug, praziquantel (PZQ). As a...
BACKGROUND
Anthelminthic treatment options against schistosomiasis are limited. The current treatment relies almost exclusively on a single drug, praziquantel (PZQ). As a consequence, the development of resistance to PZQ and limited activity of PZQ against earlier development stages are respectively a risk and a limitation to achieving the goals of the new WHO roadmap towards elimination. For the discovery of new chemical starting points, the in vitro drug screening on Schistosoma mansoni (S. mansoni) against newly transformed schistosomula (NTS) is still the most predominant approach. The use of only NTS in the initial screening limits sensitivity to potential new compounds which are predominantly active in later developmental stages. Using our recently described highly standardized, straightforward and reliable culture method that generates high rates of juvenile worms, we aimed to repurpose a subset of the National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection (340 compounds) to identify new hits with an in vitro worm culture assay.
METHODOLOGY/PRINCIPAL FINDINGS
Cercariae were mechanically transformed into skin-stage (SkS) schistosomula and continuously cultured for 3-6 weeks to the liver stage (LiS). A commercial source of serum was identified, and decrease of NTS/well along with optimal drug testing conditions was established to test compounds on early and late LiS worms. The library was screened in 96-well format assays using praziquantel (PZQ) as a positive control. Primary screening allowed a 5.9% hit rate and generated two confirmed hits on adult worms; a prophylactic antianginal agent and an antihistaminic drug.
CONCLUSION
With this standardized and reliable in vitro assay, important S. mansoni developmental stages up to LiS worms can be generated and cultured over an extended period. When exposed to a subset of the NCATS Pharmaceutical Collection, 3 compounds yielded a defined anti-schistosomal phenotype on juvenile worms. Translation of activity on perfused adult S. mansoni worms was achieved only for perhexiline (a prophylactic antianginal agent) and astemizole (an antihistaminic drug).
Topics: Animals; Astemizole; Drug Evaluation, Preclinical; In Vitro Techniques; Perhexiline; Schistosoma mansoni; Schistosomiasis mansoni; Schistosomicides
PubMed: 34033658
DOI: 10.1371/journal.pntd.0009432 -
Scientific Reports Dec 2020Cytochrome P450 2J2 (CYP2J2) is responsible for the epoxidation of endogenous arachidonic acid, and is involved in the metabolism of exogenous drugs. To date, no crystal...
Cytochrome P450 2J2 (CYP2J2) is responsible for the epoxidation of endogenous arachidonic acid, and is involved in the metabolism of exogenous drugs. To date, no crystal structure of CYP2J2 is available, and the proposed structural basis for the substrate recognition and specificity in CYP2J2 varies with the structural models developed using different computational protocols. In this study, we developed a new structural model of CYP2J2, and explored its sensitivity to substrate binding by molecular dynamics simulations of the interactions with chemically similar fluorescent probes. Our results showed that the induced-fit binding of these probes led to the preferred active poses ready for the catalysis by CYP2J2. Divergent conformational dynamics of CYP2J2 due to the binding of each probe were observed. However, a stable hydrophobic clamp composed of residues I127, F310, A311, V380, and I487 was identified to restrict any substrate access to the active site of CYP2J2. Molecular docking of a series of compounds including amiodarone, astemizole, danazol, ebastine, ketoconazole, terfenadine, terfenadone, and arachidonic acid to CYP2J2 confirmed the role of those residues in determining substrate binding and specificity of CYP2J2. In addition to the flexibility of CYP2J2, the present work also identified other factors such as electrostatic potential in the vicinity of the active site, and substrate strain energy and property that have implications for the interpretation of CYP2J2 metabolism.
Topics: Arachidonic Acid; Astemizole; Butyrophenones; Catalytic Domain; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Humans; Hydrophobic and Hydrophilic Interactions; Kinetics; Molecular Docking Simulation; Oxidation-Reduction; Piperidines; Protein Binding; Substrate Specificity
PubMed: 33335233
DOI: 10.1038/s41598-020-79284-0 -
Computers in Biology and Medicine Jul 2022GLS1 enzymes (Glutaminase C (GAC) and kidney-type Glutaminase (KGA)) are gaining prominence as a target for tumor treatment including lung, breast, kidney, prostate, and...
GLS1 enzymes (Glutaminase C (GAC) and kidney-type Glutaminase (KGA)) are gaining prominence as a target for tumor treatment including lung, breast, kidney, prostate, and colorectal. To date, several medicinal chemistry studies are being conducted to develop new and effective inhibitors against GLS1 enzymes. Telaglenastat, a drug that targets the allosteric site of GLS1, has undergone clinical trials for the first time for the therapy of solid tumors and hematological malignancies. A comprehensive computational investigation is performed to get insights into the inhibition mechanism of the Telaglenastat. Some novel inhibitors are also proposed against GLS1 enzymes using the drug repurposing approach using 2D-fingerprinting virtual screening method against 2.4 million compounds, application of pharmacokinetics, Molecular Docking, and Molecular Dynamic (MD) Simulations. A TIP3P water box of 10 Å was defined to solvate both enzymes to improve MD simulation reliability. The dynamics results were validated further by the MMGB/PBSA binding free energy method, RDF, and AFD analysis. Results of these computational analysis revealed a stable binding affinity of Telaglenastat, as well as an FDA approved drug Astemizole (IC ∼ 0.9 nM) and a novel para position oriented methoxy group containing Chembridge compound (Chem-64284604) that provides an effective inhibitory action against GAC and KGA.
Topics: Humans; Male; Cell Line, Tumor; Drug Repositioning; Enzyme Inhibitors; Glutaminase; Molecular Docking Simulation; Molecular Dynamics Simulation; Reproducibility of Results
PubMed: 35654625
DOI: 10.1016/j.compbiomed.2022.105669 -
International Journal of Cancer Jul 2019Polycomb group proteins are important epigenetic regulators for cell proliferation and differentiation, organ development, as well as initiation and progression of...
Polycomb group proteins are important epigenetic regulators for cell proliferation and differentiation, organ development, as well as initiation and progression of lethal diseases, including cancer. Upregulated Polycomb group proteins, including Enhancer of zeste homolog 2 (EZH2), promote proliferation, migration, invasion and metastasis of cancer cells, as well as self-renewal of cancer stem cells. In our study, we report that EZH2 and embryonic ectoderm development (EED) indicate respective direct interaction with androgen receptor (AR). In the context of AR-positive prostate cancer, EZH2 and EED regulate AR expression levels and AR downstream targets. More importantly, we demonstrate that targeting EZH2 with the small-molecule inhibitor astemizole in cancer significantly represses the EZH2 and AR expression as well as the neoplastic capacities. These results collectively suggest that pharmacologically targeting EZH2 might be a promising strategy for advanced prostate cancer.
Topics: Animals; Astemizole; Cell Line, Tumor; Enhancer of Zeste Homolog 2 Protein; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Polycomb Repressive Complex 2; Prostatic Neoplasms; Receptors, Androgen; Sequence Analysis, RNA; Signal Transduction; Xenograft Model Antitumor Assays
PubMed: 30628724
DOI: 10.1002/ijc.32118 -
ACS Medicinal Chemistry Letters Aug 2021In the context of drug repositioning and expanding the existing structure-activity relationship around astemizole (AST), a new series of analogues were designed,...
In the context of drug repositioning and expanding the existing structure-activity relationship around astemizole (AST), a new series of analogues were designed, synthesized, and evaluated for their antiplasmodium activity. Among 46 analogues tested, compounds , , and displayed high activities against asexual blood stage parasites (NF54 IC = 0.025-0.043 μM), whereas amide compound additionally showed activity against late-stage gametocytes (stage IV/V; LG IC = 0.6 ± 0.1 μM) and 860-fold higher selectivity over hERG (, SI = 43) compared to AST. Several analogues displaying high solubility (Sol > 100 μM) and low cytoxicity in the Chinese hamster ovary (SI > 148) cell line have also been identified.
PubMed: 34413963
DOI: 10.1021/acsmedchemlett.1c00328 -
Oncogene Jan 2021Ether-à-go-go-1 (EAG1), one of the potassium channels, is involved in various physiological processes and plays an important role in the tumorigenesis of many kinds of...
Ether-à-go-go-1 (EAG1), one of the potassium channels, is involved in various physiological processes and plays an important role in the tumorigenesis of many kinds of cancer. EAG1 is highly expressed in hepatocarcinoma cells and is closely related to clinical prognosis, but the molecular mechanism remains elusive. In this study, we verified that EAG1 promotes the proliferation of hepatocellular carcinoma (HCC) both in vitro and in vivo. It promotes cell cycle progression by inhibiting the ubiquitination of SKP2. In addition, EAG1 promotes the migration and invasion of HCC by promoting cell pseudopod formation. Furthermore, in a high-pressure plasmid-injected mouse liver orthotopic carcinoma model, astemizole, an EAG family blocker, can significantly inhibit the formation of liver cancer. Meanwhile, liver-specific EAG1 knockout mice show resistance to hepatocarcinogenesis. This research demonstrated that EAG1 plays an important role in the progression of HCC, and could be a potential therapeutic target for HCC.
Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Ether-A-Go-Go Potassium Channels; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Male; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Prognosis; S-Phase Kinase-Associated Proteins; Ubiquitination; Up-Regulation
PubMed: 33097858
DOI: 10.1038/s41388-020-01522-6 -
Journal of Pharmacological and... 2020Any adverse event is reliant on three properties: the appropriate pharmacology to trigger the event, the appropriate exposure of compound, and intrinsic patient factors....
Any adverse event is reliant on three properties: the appropriate pharmacology to trigger the event, the appropriate exposure of compound, and intrinsic patient factors. Each alone is necessary but insufficient to predict the event. The Comprehensive in vitro Proarrhythmia Assessment (CiPA) initiative attempts to predict the risk of torsade de pointes (TdP) by focusing on an in-silico model with thresholds determined at modest multiples of the therapeutic exposure for the parent molecule. This emphasizes the pharmacologic properties necessary for TdP but does not account for situations where clinical exposure may be higher, or where hERG potassium channel active metabolites are involved. Could accounting for clinical worst-case scenarios and metabolites, as is already standard practice in thorough QTc studies, improve the prediction algorithm? Terfenadine, a drug classed as "Intermediate" risk by CiPA, was assessed differently in the in-silico model validation. The clinical concentration of terfenadine used for the model was the exposure in the presence of metabolic inhibition representing a 14 to 40-fold increase in exposure compared to the therapeutic plasma concentration. However, several other "Intermediate" risk compounds are also known to be sensitive to metabolic inhibition and/or to have therapeutically active major metabolites, some of which are known to block hERG. Risperidone and astemizole are relevant examples. If only parent exposure is used to calculate a therapeutic window, risperidone has a relatively large multiple between clinical exposure and the hERG potency. Using this exposure of risperidone, the drug borders the "Intermediate" and "Low/No" risk categories for the CiPA in-silico model's TdP metric. The desmethyl metabolite of astemizole likely contributes significantly to the effects on cardiac repolarization, being equipotent on hERG but circulating at much higher levels than parent. Recalculating the TdP metric and margin values for terfenadine, risperidone and astemizole using the unbound concentration normally associated with treatment and a clinical worst case changes the qNet metric to higher risk values and illustrates the potential benefit to the algorithm of consistently using a clinical high exposure scenario accounting for all "hERG-active species". This exercise suggests repeating the model qualification accounting for clinical exposures and metabolites under 'stressed' scenarios would improve prediction of the TdP risk.
Topics: Astemizole; Computer Simulation; Drug-Related Side Effects and Adverse Reactions; Electrocardiography; Humans; Risk Assessment; Risperidone; Terfenadine; Torsades de Pointes
PubMed: 31730936
DOI: 10.1016/j.vascn.2019.106654 -
Biomedicines Jul 2020Adrenocortical carcinoma (ACC) presents a high risk of relapse and metastases with outcomes not improving despite extensive research and new targeted therapies. We...
Adrenocortical carcinoma (ACC) presents a high risk of relapse and metastases with outcomes not improving despite extensive research and new targeted therapies. We recently showed that the Hedgehog receptor Patched is expressed in ACC, where it strongly contributes to doxorubicin efflux and treatment resistance. Here, we report the identification of a new inhibitor of Patched drug efflux, the anti-histaminergic drug astemizole. We show that astemizole enhances the cytotoxic, proapoptotic, antiproliferative and anticlonogenic effects of doxorubicin on ACC cells at concentrations of astemizole or doxorubicin that are not effective by themselves. Our results suggest that a low concentration of astemizole sensitizes ACC cells to doxorubicin, which is a component of the standard treatment for ACC composed of etoposide, doxorubicin, cisplatin and mitotane (EDPM). Patched uses the proton motive force to efflux drugs. This makes its function specific to cancer cells, thereby avoiding toxicity issues that are commonly observed with inhibitors of ABC multidrug transporters. Our data provide strong evidence that the use of astemizole or a derivative in combination with EDPM could be a promising therapeutic option for ACC by increasing the treatment effectiveness at lower doses of EDPM, which would reduce the severe side effects of this regimen.
PubMed: 32751066
DOI: 10.3390/biomedicines8080251 -
Journal of Medicinal Chemistry Dec 2022Iterative medicinal chemistry optimization of an ester-containing astemizole (AST) analogue with an associated metabolic instability liability led to the identification...
Iterative medicinal chemistry optimization of an ester-containing astemizole (AST) analogue with an associated metabolic instability liability led to the identification of a highly potent 3-trifluoromethyl-1,2,4-oxadiazole analogue (NF54 IC = 0.012 μM; K1 IC = 0.040 μM) displaying high microsomal metabolic stability (HLM CL < 11.6 μL·min·mg) and > 1000-fold higher selectivity over hERG compared to AST. In addition to asexual blood stage activity, the compound also shows activity against liver and gametocyte life cycle stages and demonstrates efficacy in -infected mice at 4 × 50 mg·kg oral dose. Preliminary interrogation of the mode of action using live-cell microscopy and cellular heme speciation revealed that could be affecting multiple processes in the parasitic digestive vacuole, with the possibility of a novel target at play in the organelles associated with it.
Topics: Mice; Animals; Plasmodium berghei; Antimalarials; Astemizole; Plasmodium falciparum; Malaria; Disease Models, Animal
PubMed: 36507890
DOI: 10.1021/acs.jmedchem.2c01516 -
BMC Public Health Feb 2024Recently, COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, caused > 6 million deaths. Symptoms included respiratory... (Review)
Review
Recently, COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, caused > 6 million deaths. Symptoms included respiratory strain and complications, leading to severe pneumonia. SARS-CoV-2 attaches to the ACE-2 receptor of the host cell membrane to enter. Targeting the SARS-CoV-2 entry may effectively inhibit infection. Acid sphingomyelinase (ASMase) is a lysosomal protein that catalyzes the conversion of sphingolipid (sphingomyelin) to ceramide. Ceramide molecules aggregate/assemble on the plasma membrane to form "platforms" that facilitate the viral intake into the cell. Impairing the ASMase activity will eventually disrupt viral entry into the cell. In this review, we identified the metabolism of sphingolipids, sphingolipids' role in cell signal transduction cascades, and viral infection mechanisms. Also, we outlined ASMase structure and underlying mechanisms inhibiting viral entry 40 with the aid of inhibitors of acid sphingomyelinase (FIASMAs). In silico molecular docking analyses of FIASMAs with inhibitors revealed that dilazep (S = - 12.58 kcal/mol), emetine (S = - 11.65 kcal/mol), pimozide (S = - 11.29 kcal/mol), carvedilol (S = - 11.28 kcal/mol), mebeverine (S = - 11.14 kcal/mol), cepharanthine (S = - 11.06 kcal/mol), hydroxyzin (S = - 10.96 kcal/mol), astemizole (S = - 10.81 kcal/mol), sertindole (S = - 10.55 kcal/mol), and bepridil (S = - 10.47 kcal/mol) have higher inhibition activity than the candidate drug amiodarone (S = - 10.43 kcal/mol), making them better options for inhibition.
Topics: Humans; COVID-19; Molecular Docking Simulation; SARS-CoV-2; Sphingomyelin Phosphodiesterase; Ceramides; Sphingolipids
PubMed: 38321448
DOI: 10.1186/s12889-024-17747-z